Metabolism of N-Glycolylneuraminic Acid in Human and Nonhuman Cells, and Potential Relationships to Human Disease

Abstract

N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid commonly found at the outermost position of glycan chains at the surface of most mammalian cells. The only known pathway for synthesis of Neu5Gc is the conversion of CMP-N-acetylneuraminic acid (CMP-Neu5Ac) to CMP-Neu5Gc, catalyzed by the cytidine monophospho-N-acetylneuraminic acid hydroxylase (Cmah). These CMP-activated sialic acids serve as precursors for glycan assembly in the Golgi apparatus. A degradative pathway to eliminate Neu5Gc and regulate Neu5Gc levels in mammalian cells involves enzymatic conversion of Neu5Gc to N-glycolylglucosamine-6-phosphate (GlcNGc-6P) via N-glycolylmannosamine (ManNGc) and GlcNGc. Irreversible de-N-glycolylation of GlcNGc-6P generates the common cellular metabolites glucosamine-6-phosphate and glycolate and therewith eliminates the N-glycolyl group from sialic acid and amino sugar biosynthetic pathways. Humans lack endogenous Neu5Gc biosynthesis due to an inactivating deletion in the human CMAH gene. This has been confirmed by the absence of detectable Neu5Gc in the Cmah-/- mouse model harboring the humanlike Cmah allele. However, humans incorporate exogenous Neu5Gc from animal-derived food products (primarily meats of mammalian origin) into endogenous cellular glycoconjugates despite a polyclonal anti-Neu5Gc antibody response, which makes Neu5Gc the first known “xeno-autoantigen” in humans. The metabolic pathways and potential implications for human disease are discussed.